Human tuberculosis bacteria (Mycobacterium tuberculosis) is widely known among mycobacteria, with which third part of human beings are said to be infected. Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium pinnipedii, and Mycobacterium microti are known to belong to the tuberculosis bacteria group like human tuberculosis bacteria, and are known as mycobacteria having pathogenicity against human
Multidrug chemotherapy for 6 months has been recommended as a treatment for these tuberculosis bacteria. A typical therapy comprises a treatment with 4 agents of rifampicin, isoniazid, pyrazinamide, and ethambutol (or streptomycin) for the first 2 months; and a treatment with 2 agents of rifampicin and isoniazid for the remaining 4 months.
It has been pointed out however that the medication compliance in the treatment for tuberculosis is poor due to such long-term treatment and adverse effects of the used drugs often cause the treatment to discontinue.
The adverse effects of these drugs have been reported (Nonpatent Literatures 1 and 2), for example, rifampicin has hepatic disorder, flu syndrome, drug allergy, and contraindication to combination use with other drugs caused by P450-related enzymes; isoniazid has peripheral neuropathy and serious hepatic disorder induced with a combination use with rifampicin; ethambutol has visual loss caused by optic nerve disorder; streptomycin has hearing loss caused by eighth cranial nerve involvement; pyrazinamide has hepatic disorder, gouty attack associated with the uric acid level, and vomiting. Amongst the adverse effects of the above 5 agents used as a first-line drug, in particular, hepatotoxicity commonly-caused by rifampicin, isoniazid, and pyrazinamide is known as the most frequent adverse effect.
It has been in fact reported that the cases where the standard chemotherapy cannot be carried out due to the adverse effects account for 70% of the cases where the drug administration is discontinued (about 23%, 52 cases) of the total (the total of 228 inpatient cases surveyed) (Nonpatent Literature 3).
Tuberculosis bacteria resistant to antitubercular agents, multidrug-resistant tuberculosis bacteria, for example have been recently increasing, which has made the treatment of tuberculosis more difficult.
The World Health Organization (WHO) has reported that among those who have been infected with multidrug-resistant tuberculosis (MDR-TB) resistant to potent rifampicin and isoniazid, 450,000 people have newly developed and 170,000 people have died per year, and multidrug-resistant tuberculosis patients are currently estimated as 1,500,000 in the world. An extensively-drug-resistant tuberculosis (XDR-TB) which has been resistant to many drugs has been identified, which has become a threat to public health in the world (Nonpatent Literature 4).
Third part of those who have been infected with HIV in the world has been suspected of co-infection with tuberculosis even though not progressing to active tuberculosis (Nonpatent Literature 5). Co-infection of HIV and tuberculosis is fatal, in which one disease can accelerate the progression of the other disease and tuberculosis can easily progress to active tuberculosis. In 2012, about 320,000 people died of tuberculosis associated with HIV, which means that about 25% of the death of HIV infected people were caused by tuberculosis. It has been also reported that patients infected with both HIV and tuberculosis can develop tuberculosis in 20 to 37 times higher risk than usual (Nonpatent Literature 6).
The American Thoracic Society and Centers for Disease Control and Prevention have recently reported the concept that carriage state itself of tuberculosis bacteria is a potential disease even though not developing to tuberculosis, and the usefulness of active treatment has been established for patients with a higher risk of developing to the disease.
In view of the current circumstances, a desired profile for antitubercular agents includes (1) those effective for multidrug-resistant tuberculosis bacteria, (2) those which enable a short-term chemotherapy, (3) those with less adverse effects, (4) those effective for latent tuberculosis infection (LTBI).
Mycobacterium avium and Mycobacterium intracellulare, which are responsible bacteria for recently increasing MAC symptom (Mycobacterium avium-intracellulare complex symptom), as well as other non-tuberculous mycobacteria such as Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium smegmatis, and Mycobacterium aurum have been known as bacteria having pathogenicity in human.
A typical chemotherapy of lung MAC symptom is polypharmacy based on three drugs of rifampicin, ethambutol, and clarithromycin, and streptomycin or kanamycin is, if needed, used in combination. Another treatment for non-tuberculous mycobacteria symptom currently includes combination use with an antitubercular agent such as rifampicin, isoniazid, ethambutol, streptomycin, kanamycin, a therapeutic agent for common bacterial infection such as a newquinolone agent, a macrolide antibacterial agent, an aminoglycoside antibacterial agent, and a tetracycline antibacterial agent.
It has been reported however that the treatment for non-tuberculous mycobacteria needs a longer-term medication than that in common bacterial infection, the treatment tends to become refractory, and some have resulted in death. To solve the circumstances, a development of more potent drugs has been desired.
For example, Patent Literature 1 discloses that 6-nitro-1,2,3,4-tetrahydro[2,1-b]imidazopyrane compounds have a bactericidal activity against tuberculosis bacteria (H37Rv strain) and multidrug-resistant tuberculosis bacteria in vitro and a therapeutic effect in oral administration for a tuberculosis-infected animal model, and thus they are useful as an antitubercular agent.
Patent Literatures 2 and 3 disclose that 2,3-dihydroimidazo[2,1-b]oxazole compounds have a bactericidal activity against tuberculosis bacteria, multidrug-resistant tuberculosis bacteria, and atypical mycobacteria.
Patent Literature 4 discloses that nitroimidazooxazine and nitroimidazooxazole compounds can be used as a medicament against human tuberculosis bacteria (Mycobacterium tuberculosis).
Patent Literature 5 discloses that 6,7-dihydroimidazo[2,1-b][1,3]oxazine compounds have an excellent bactericidal activity against tuberculosis bacteria and multidrug-resistant tuberculosis bacteria.
The compounds disclosed in the above references, however, structurally differ from and are not similar to the compound of the present invention.